Between 100,000 and 250,000 patients with alcohol use disorder develop sepsis annually. Septic patients with chronic alcohol abuse have increased mortality and severity of multiple organ dysfunction compared to septic patients without a history of alcohol abuse. This proposal aims to understand why chronic alcohol abuse worsens outcomes in sepsis, as this common -- and deadly -- scenario is responsible for thousands of deaths per year and poses a huge financial burden on the U.S. healthcare system. In the previous cycle of finding, we characterized murine models that replicate the increased mortality seen in alcoholic septic patients compared to patients who develop sepsis without a history of alcohol abuse. Importantly, while the majority of organs have similar function and histology between alcohol/septic and water/septic mice, both gut integrity and the immune system are severely dysregulated in alcohol/septic mice. This is manifested in two complementary ways. First, abnormalities in gut integrity and the immune response are exacerbated in alcohol/septic mice compared to water/septic mice. Second, there are a number of differences identified only in alcohol/septic mice that are not present with either alcohol in isolation or sepsis in isolation. Notably, intestinal permeability is worsened in alcohol/sepsis, and this is associated with changes in the gut tight junction that are specific to the combination of alcohol and sepsis. Blockade of the co-inhibitory receptor CTLA-4 is also significantly more efficacious in alcohol/sepsis than water/sepsis, associated with differences in regulatory T cells and effector CD4+ cells. Finally, CD43 (which is implicated in T cell homing and activation) expression is delayed in alcohol/sepsis and survival is altered in septic CD43-/- mice. The proposal seeks to understand the mechanisms underlying these specific differences in gut permeability and the adaptive immune response in alcohol/septic mice. Since septic hosts with alcohol use disorders appear to respond differently to a septic insult than those without a history of alcohol abuse, this may require a different therapeutic approach than would be needed in a ?typical? septic host. As such, this proposal will elucidate mechanisms underlying gut and immune dysfunction during alcohol/sepsis with the ultimate goal of improving outcomes in this common and very vulnerable population.